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P1‐073: PREPARATION OF ONE MONTH RELEASE DONEPEZIL INJECTABLE FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND ITS PHARMACOKINETICS IN A RAT MODEL
Author(s) -
Yoon Kwonhyeok,
Seol Eunyoung,
Lee Soojung,
Lee Heeyong
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.075
Subject(s) - donepezil , pharmacokinetics , pharmacology , materials science , chemistry , biomedical engineering , chromatography , medicine , disease , dementia
humanized [KAL-ABP-BBB(H)] proteins were produced in CHO cells. BBB-permeability was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat and mouse) models. Aß binding was determined by ELISA, Western blot overlay and immunohistochemical methods. Serum, CSF and brain levels of systemically dosed KAL-ABP-BBB constructs and Aßwere assessed by nanoLC-MRM, ELISA and Western blot. Results: Both KALABP-BBB bi-functional fusion proteins expressed in CHO cells retained Aß-oligomer binding activity and BBB-permeability in vitro. After systemic dosing, both KAL-ABP-BBB versions demonstrated identical long serum pharmacokinetics in rats and were detected in CSF, cortex and hippocampus of na€ıve and transgenic mice. In transgenic mice, treatment with either variant of KAL-ABP-BBB resulted in a significant (w50%) reduction of Aß levels in the CSF suggesting in vivo target engagement. The ability of each variant to engage naturally occurring Aß was further shown after brain microinjection in live animals. Translational studies in aged dogs, which exhibit elevated levels of Aß (identical to human Aß), demonstrated similar serum PK to that observed in rats,>20-fold increased CSF exposure compared to control fusion protein, as well as a reduction in CSF levels of Aß, indicating target engagement. Conclusions: The study demonstrates translation of results (serum PK, enhanced CNS exposure, and lowering of Aß) obtained with KAL-ABPBBB (M) in rodent species to aged dogs. Chakravarthy et al., J. Neurochem 126, 415, 2013. Biochem. Biophys. Res. Commun. 445, 656, 2014.